Tendinopathy and tendon rupture are common painful and debilitating clinical problems associated with frequently experienced high tensile loads, structural and material inhomogeneity, and inadequate healing responses to injury. Studies have therefore evaluated mechanical and structural degeneration of ligaments and tendons in response to overuse and cyclic loading to investigate mechanism of initiation and progression of tendinopathy. Surface strain in the tendon has been quantified to extrapolate its load bearing capacity and likelihood of damage initiation or progression. Overall molecular expression has also been evaluated in response to tendon loading to make conclusions regarding mechanisms of tendon damage and repair. Despite insight gained from these studies, the relationship between local tendon strain, structural damage, and the local molecular response to sub-rupture fatigue damage has not been established. Establishing the direct relationship between the molecular and structural changes and the load bearing capacity of the tendon will lend insight into the mechanisms of tendon damage and repair. Limitations of in-vivo strain measurement methods and molecular analyses preclude evaluation of the relationship between the molecular response and the magnitude and direction of the local tendon strain in-vivo over time. Therefore the general objective of this proposal is to quantify the relationship between the local strain in rat patellar tendons and the local molecular response within the tendon in an in-vivo fatigue damage model. The local molecular response of the tendon will be measured after fatigue loading, and over time to determine the response to damage and repair. Techniques will be developed to measure high resolution in-vivo tendon strain and structural damage which will be related to the spatial molecular response. This will provide the missing mechanical and structural context to interpret the molecular response of tendon to damage and healing. Evaluating the local instead of bulk tissue mechanics and molecular response will provide insight into whether any molecular changes associated with sub-rupture fatigue damage repair in bulk tissue analysis stem from load bearing or mechanically deficient regions. While the bulk molecular response of the tendon may be indicative of repair or remodeling, data from the proposed study will show whether a damaged mechanically deficient region can heal or only be further damaged. Evaluating these relationships over time will explore mechanisms of tendon repair which could influence development of effective treatment. PUBLIC HEALTH RELEVANCE: Tendinopathy is a common and debilitating clinical problem. The goal of this proposal is to quantify the local relationship between strain, molecular response, and structural changes within the tendon in-vivo after fatigue loading and over time to determine the response to damage and repair. This will provide the missing mechanical and structural context to interpret the molecular response of the tendon to damage and repair.